In a study published online in Nature today, researchers describe the discovery and development of the melanoma drug PLX4032. Dr. Gideon Bollag of Plexxikon and his colleagues reveal the drug’s chemical structure and describe how PLX4032 functions in the body. The authors detail their efforts to determine the proper doses for patients, including a critical reformulation of the drug that allowed patients to achieve the high levels needed for clinical responses.
Targeted Drug for Melanoma Shows Promise in Early Clinical Testing
The vast majority of patients with advanced melanoma who received an experimental targeted drug called PLX4032 responded to the treatment in a phase I clinical trial, researchers announced last month. The drug targets a common genetic change in melanoma tumors, and 26 of 32 patients (81 percent) who were treated with the recommended phase II dose had a partial or complete response. The tumors of some patients even went away, at least temporarily.
“The responses to this drug are clearly different than what other drugs have done for melanoma,” said Dr. Keith Flaherty of Massachusetts General Hospital (MGH), who co-led the multicenter trial. “Some patients are getting quite durable responses that are blowing the doors off what previous therapies have accomplished.”
The drug is a pill that primarily blocks growth-promoting signals caused by a mutation in a gene called BRAF. Based on the trial results, reported in the August 26 New England Journal of Medicine (NEJM), the researchers have launched a phase III study to see whether the drug can improve survival in patients whose tumors harbor the genetic mutation, known as V600E.
“The trial was needed to determine whether the drug is really altering the natural history of the disease in a profound way,” Dr. Flaherty noted. Although melanoma is treatable when detected early, the cancer is often fatal within a year once it has spread to other parts of the body. And only 10 to 20 percent of patients with advanced melanoma respond to FDA-approved drugs.
Patients in the phase I trial had seen their cancers progress despite one or more previous therapies, and some patients were running out of treatment options. In an extension cohort of 32 patients who carried the V600E mutation, the median time from initial response to PLX4032 until disease progression was more than 7 months and the longest responders have been taking the drug for approximately 2 years.
“These results represent a major breakthrough and provide proof of the principle that the treatment of metastatic melanoma can be individualized for a substantial percentage of patients,” said Drs. Kieran S.M. Smalley and Vernon K. Sondak of the H. Lee Moffitt Cancer Center & Research Institute in an accompanying editorial. “Over the past decade, great strides have been made in unraveling the unique biology of melanoma, and the research investment is paying off,” they wrote.
In 2002, researchers discovered that approximately half of human melanomas harbor the V600E mutation in BRAF that activates the gene. A non-specific BRAF inhibitor called sorafenib (Nexavar) was subsequently tested in the disease, but the results were not encouraging. Meanwhile, activating mutations in a gene called KIT were identified in a minority of melanoma cases, and studies have found that imatinib therapy leads to tumor regression in these patients.
In the future, patients with metastatic melanoma will likely be screened for mutations in key genes before starting on a therapy, the editorial predicts. (This is already happening for BRAF.) More work is needed to understand why some patients with the V600E mutation did not respond to the drug and why some developed resistance, Drs. Smalley and Sondak noted.
In the dose-escalation phase of the study, which tested increasing doses in 49 patients, the researchers observed tumor shrinkage at all sites of metastatic disease including the liver, small bowel, and bone. After the dose to be used in the phase II trial was determined, the drug was evaluated in the 32 additional melanoma patients with BRAF mutations. Among this group, 24 had partial responses and 2 had complete responses.
“We’re all excited about the responses we’ve seen in the phase I trial, but in melanoma we’ve learned over and over again that the responses don’t necessarily lead to improvements in overall survival,” said the study’s senior author, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center. “So the purpose of the phase III trial is to see if we’re getting patients to live longer.”
In June, researchers announced that ipilimumab, a treatment that targets the immune system, helped patients with advanced melanoma live longer. Together, ipilimumab and PLX4032 have changed the landscape of melanoma research and raised the prospect that the new agents could be tested in combination or sequentially, said Dr. Claudio Dansky Ullmann, who oversees melanoma trials for the NCI Cancer Therapy Evaluation Program.
“These studies have opened the doors to a lot of possibilities for treating metastatic melanoma,” said Dr. Dansky Ullmann. “We can now test many treatments that were not available or proven until recently. This area of research is taking off.”
Several targeted therapies are in development for melanoma, including other BRAF inhibitors and agents directed at other pathways in the disease, he noted. Researchers are hopeful that different types of drugs, such as targeted therapies and immune-based therapies, could be combined to improve survival.
“This is all so new—there are many unknowns that will need to be clarified by future studies,” cautioned Dr. Dansky Ullmann. “And we need to get smarter about identifying specific patient populations in which to test a particular combination.”
The side effects of PLX4032 were mostly mild and included rash, nausea, fatigue, and low-grade tumors on the skin called squamous cell carcinomas. These were removed easily and did not cause any of the patients to discontinue treatment, the researchers said.
Melanoma is a genetically complex disease and determining which pathways are most important for therapies will require further research, Dr. Flaherty said. “Other pathways are definitely involved in the disease,” he added, noting that trials are under way to combine a BRAF inhibitor with an inhibitor of the MEK pathway.
“Most people were skeptical that targeting a single gene would have an impact,” Dr. Sondak said in an interview. Even the researchers themselves wondered whether the drug would work as they hoped. Many potential chemotherapy drugs for melanoma have looked promising in the lab, only to disappoint when tested in patients. PLX4032 could have been just another one of these.
There were other reasons to be skeptical, noted Dr. Chapman. No one knew whether blocking signals from the mutant BRAF gene would make a difference to patients. Mutations in the BRAF gene occur early in the development of the disease (they are also present in benign skin growths such as moles), and the researchers worried that advanced tumors might be driven by other genetic changes. What’s more, mice with BRAF mutations do not always develop a rodent form of melanoma.
“All of this information was telling us that BRAF mutations were necessary—but not sufficient—to make a cell a melanoma,” explained Dr. Chapman. If melanoma tumors were not dependent on signals from a mutant BRAF gene, there was a real possibility that blocking these signals might have no effect on the tumor.
“The astounding part of the study was that the drug worked as intended,” said Dr. Chapman.
A turning point in the trial, which was sponsored by Plexxikon and Roche, was the development of a new formulation of PLX4032 that allowed patients to achieve higher blood levels of the drug. (See the sidebar.) In the phase III trial, the drug is being compared to dacarbazine, which is a standard chemotherapy treatment for melanoma.
The researchers want to know as soon as possible whether the drug is increasing survival compared with standard treatment. Patients need new therapies for this disease, they say, and for the first time clinical trials are providing promising options.
“We now have a totally different mindset than we’ve ever had before for treating melanoma,” Dr. Flaherty said. “But until patients are in long remission, it’s hard to celebrate too much.”
—Edward R. Winstead